HPN heterodimer cleaves pro-MST1 to form MST1 dimer

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R-HSA-6800198
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Reaction
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Homo sapiens
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Hepsin (HPN, aka TMPRSS1) is a cell surface-expressed chymotrypsin-like serine protease and a member of the family of type II transmembrane serine proteases (TTSP). The HPN zymogen is activated autocatalytically by cleavage at Arg162–Ile163, forming a heterodimeric enzyme (Tsuji et al. 1991, Torres-Rosado et al. 1993). HPN plays an essential role in cell growth and maintenance of cell morphology and is highly upregulated in prostate cancer and promotes tumor progression and metastasis. Located on the cell surface, HPN can activate fibrinolytic enzymes, matrix metalloproteases and latent forms of growth factors such as hepatocyte growth factor-like protein (MST1, aka macrophage stimulatory protein, MSP). MST1 is a plasminogen-related growth factor and ligand for the receptor tyrosine kinase (MST1R, RON). The MST1/MST1R (MSP/RON) signaling system promotes wound healing and invasive tumor growth and suppresses proinflammatory immune response. For MST1 to bind MST1R, the inactive single-chain form (pro-MST1) must be cleaved into the disulfide-linked alpha-beta heterodimer by HPN (Ganesan et al. 2011). The Kunitz-type protease inhibitors 1 and 2 (SPINT1 and 2, aka HAI1 and 2) are inhibitors of HPN activity (Kirchhofer et al. 2005).

The non-synonymous coding variant in MST1 (R689C) has been associated with genetic susceptibility to both Crohn's disease and ulcerative colitis, two major types of inflammatory bowel disease (IBD). The R689C variant reduces the amount of circulating MST1 thereby reducing MST1R activity and down-regulation of the MST1/MST1R signaling pathway (McGovern et al. 2010, Gorlatova et al. 2011, Kauder et al. 2013).

Literature References
PubMed ID Title Journal Year
22087277 Protein characterization of a candidate mechanism SNP for Crohn's disease: the macrophage stimulating protein R689C substitution

Gorlatova, N, Chao, K, Pal, LR, Araj, RH, Galkin, A, Turko, I, Moult, J, Herzberg, O

PLoS ONE 2011
15792801 Hepsin activates pro-hepatocyte growth factor and is inhibited by hepatocyte growth factor activator inhibitor-1B (HAI-1B) and HAI-2

Kirchhofer, D, Peek, M, Lipari, MT, Billeci, K, Fan, B, Moran, P

FEBS Lett. 2005
8346233 Hepsin, a putative cell-surface serine protease, is required for mammalian cell growth

Torres-Rosado, A, O'Shea, KS, Tsuji, A, Chou, SH, Kurachi, K

Proc. Natl. Acad. Sci. U.S.A. 1993
24409221 Functional consequences of the macrophage stimulating protein 689C inflammatory bowel disease risk allele

Kauder, SE, Santell, L, Mai, E, Wright, LY, Luis, E, N'Diaye, EN, Lutman, J, Ratti, N, Sa, SM, Maun, HR, Stefanich, E, Gonzalez, LC, Graham, RR, Diehl, L, Faubion, WA, Keir, ME, Young, J, Chaudhuri, A, Lazarus, RA, Egen, JG

PLoS ONE 2013
1885621 Hepsin, a cell membrane-associated protease. Characterization, tissue distribution, and gene localization

Tsuji, A, Torres-Rosado, A, Arai, T, Le Beau, MM, Lemons, RS, Chou, SH, Kurachi, K

J. Biol. Chem. 1991
20228799 Genome-wide association identifies multiple ulcerative colitis susceptibility loci

McGovern, DP, Gardet, A, Törkvist, L, Goyette, P, Essers, J, Taylor, KD, Neale, BM, Ong, RT, Lagacé, C, Li, C, Green, T, Stevens, CR, Beauchamp, C, Fleshner, PR, Carlson, M, D'Amato, M, Halfvarson, J, Hibberd, ML, Lördal, M, Padyukov, L, Andriulli, A, Colombo, E, Latiano, A, Palmieri, O, Bernard, EJ, Deslandres, C, Hommes, DW, de Jong, DJ, Stokkers, PC, Weersma, RK

Nat. Genet. 2010
21875933 Proteolytic activation of pro-macrophage-stimulating protein by hepsin

Ganesan, R, Kolumam, GA, Lin, SJ, Xie, MH, Santell, L, Wu, TD, Lazarus, RA, Chaudhuri, A, Kirchhofer, D

Mol. Cancer Res. 2011
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Title
serine-type endopeptidase activity of HPN heterodimer [plasma membrane]
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